U.S. Food and Drug Administration, U.S. Office of Dietary Supplements at the National Institutes of Health, and the New York Academy of Sciences
Probiotic Foods and Supplements: The Science and Regulations of Labeling
Posted October 20, 2010
The health properties of foods containing probiotics are receiving increased attention from consumers who are interested in improving their health by improving their diets. The identities of the microorganisms in many of these foods have been known since the 19th and 20th centuries, but with the advent of molecular biological techniques our capacity to characterize them has increased greatly. These techniques make it possible for probiotics makers to ensure the quality and safety of their products more rigorously than ever before. At the same time, the industry is receiving increased scrutiny from regulatory officials, who are charged with ensuring that these products contain what they say they do, and provide the benefits that are described on labels and in advertisements.
On June 12, 2010, manufacturers of probiotics products, regulatory officials, microbiologists, and others with an interest in probiotics labeling met to discuss this aspect of the industry. Representatives of regulatory agencies, including the U.S. Food and Drug Administration (FDA) and the Federal Trade Commission, laid out current agency guidance and discussed the precedents set by similar products in developing standards for probiotics labeling and advertising. In later sessions, microbiologists described how best to use recent scientific advances to identify and characterize the microorganisms present in probiotic foods and supplements. Such measures will provide assurance to consumers and regulatory officials alike that probiotic products contain the organisms that are described on their labels.
Use the tabs above to find a meeting report and multimedia from this event.
Presentations are available from:
Elizabeth Rahavi (International Food Information Council)
Kenneth M. Taylor (Center for Food Safety and Applied Nutrition)
Richard L. Cleland (Federal Trade Commission)
Geraldine A. June (U.S. Food & Drug Administration)
Charles Franz (Max Rubner-Institut, Federal Institute of Nutrition and Food)
Brian Beck (American Type Culture Collection)
Duane Charbonneau (Procter & Gamble)
Session I Panel Discussion
Session II Panel Discussion
Note: The views expressed by panelist Linda Duffy during the Session I discussion do not necessarily reflect the official policies of the National Center for Complementary and Alternative Medicine (NCCAM); nor does mention of trade names, commercial practices, or organizations imply endorsement by NCCAM.
The Science and Regulations of Probiotic Food and Supplement Product Labeling
By Mary Ellen Sanders (Dairy and Food Culture Technologies, Centennial, Colorado) and Dan Levy (U.S. Food and Drug Administration, College Park, Maryland)
Probiotics: From Bench to Market
By Marguerite Klein (National Institutes of Health, Bethesda, Maryland), Mary Ellen Sanders (Dairy and Food Culture Technologies, Centennial, Colorado), Tri Duong (Texas A&M University, College Station, Texas), and Howard A. Young (National Cancer Institute, National Institutes of Health, Bethesda, Maryland)
Conference presented by:
eBriefing sponsored by:
Note: This eBriefing is supported by individual and independent organizations. Support for this eBriefing by any one organization does not endorse the commercial practices or products of the other independent supporting organizations.
- 00:011. Introduction
- 00:402. Who regulates probiotics?
- 01:303. Different rules for advertising and labeling
- 03:204. Regulatory framework
- 04:425. Expressed vs. implied claims
- 09:176. Determining the reasonable basis of substantiation
- 10:587. Therapeutic claims
- 12:388. Sale of products on the internet
- 14:389. Qualified claims
- 15:4510. Responders vs. non-responders
- 17:0011. Flawed scientific evidenc
- 00:011. Introduction
- 00:302. Probiotics and labeling
- 02:233. Bacterial systematics
- 04:554. Phylo-phenetic concept
- 06:325. International code of nomenclature
- 08:466. Gram-positive eubacteria
- 09:407. Phylum firmicutes
- 11:008. Species used as probiotics
- 11:369. Genus Lactobacillus
- 12:3210. Comparative genomics of Lactobacillus
- 17:4411. Genus Bifidobacterium
- 19:3412. Recommendation
- 00:011. Introduction
- 01:402. FDA laws and regulations
- 02:113. What is food?
- 02:444. Mandatory labeling
- 03:555. Statement of identity
- 05:566. Common or usual names
- 07:077. How is a common or usual name established?
- 10:348. Ingredient labeling
- 15:129. How some names have been established or permitted
- 17:4510. Considerations for naming of probiotic
- 00:011. Introduction
- 00:482. Classification of consumer product health claim perception
- 04:533. Can probiotic health claims be substantiated
- 10:144. Is there enough evidence for the health benefits of probiotics?
- 12:255. Gap between science and claims
- 23:406. How is the FTC rated at doing its job
- 30:137. Making truthful claims to the consumers about health benefits
- 34:108. Is there a way to substantiate structure function claims?
- 38:199. Reduction of risk of cold as an structure function endpoint
- 40:0810. Intended use vs. tested use of product
- 41:2711. How is a cold diagnosed?
- 44:0012. Regultaion of probiotics based on intended use
- 48:1513. What happens if an expert panel interprets data differently than FDA
- 00:011. Introduction
- 00:292. How appropriate is it to have a trade name?
- 01:333. What's rational way of deciding that two strains are chemically different?
- 06:184. How much testing needs to be done to show two strains have similar properties?
- 10:105. Guidelines for indicating multiple strains and levels
- 14:466. What is an outside overage limit?
- 19:177. What are the minimum requirements to show "no change"?
- 20:388. How to show ingested organism is different than that consumed?
- 29:499. Monitoring of genomic variations
- 32:4910. What regulations affect a product compostition throughout its shelf life?
- 39:3711. Labeling shelf life concentrations
- 45:5612. Labeling of probiotics and cultured foods
- 51:5713. Yogurt and structure function claims
- 54:2014. Is the use of the term "probiotics" a structure function claim
- 00:011. Introduction
- 01:252. Functional foods media coverage
- 03:363. Consumer awareness: food and health
- 05:134. America's top health concerns
- 06:225. What role does food play in health
- 08:166. Food and its associated benefits
- 10:067. What is digestive health?
- 12:088. Health-benefit pairing
- 14:179. Building food and nutrition messages
- 15:1010. Source of inormation guiding consumer's
- 15:4411. Food and beverage package information
- 17:2412. Number one factor influencing purchases
- 18:2413. Summar
- 00:011. Introduction
- 00:252. Probiotics ingredient notifications
- 03:023. Structure/function regulation
- 04:394. What is the substantiation standard?
- 07:205. Identifying the meaning of the claim
- 09:476. Relationship of the evidence to the claim
- 11:387. Quality of substantiation evidence
- 12:338. Evidence that may substantiate a claim
- 14:149. Background information to support a claim
- 16:1410. Factors affecting study quality
- 17:3911. Foreign research
- 17:5512. Totality of evidence
- 18:3113. Summar
Websites and Other Resources
American Type Culture Collection
Nonprofit organization that archives and curates bacterial strains and other types of biological material
An Introduction to Probiotics
Health information on probiotics provided by NCCAM
DSMZ Bacterial Nomenclature
Resource provided by the German Collection of Microorganisms and Cell Cultures
Federal Trade Commission
Federal agency that oversees truth in advertising
Forces Shaping Bacterial Systematics
Recent perspective on the changing field of microbial taxonomy (PDF, 172 KB)
Guidance on the scientific requirements for health claims related to gut and immune function
European Food Safety Authority guidance with relevance for probiotics (PDF, 76 KB)
International Food Information Council
Organization that provides up-to-date science-based information on food safety and nutrition for consumers, health professionals and the media
International Union of Microbiological Societies (IUMS)
Major activities include the classification and nomenclature of bacteria, fungi and viruses, food microbiology, culture collections, and biological standardization
International Journal of Systematic and Evolutionary Microbiology
Official publication of the International Committee on Systematics of Prokaryotes (ICSP)and the Bacteriology and Applied Microbiology Division of the IUMS
International Journal of Food Microbiology
Official journal of the IUMS and the International Committee on Food Microbiology and Hygiene (ICFMH)
International Scientific Association for Probiotics and Prebiotics
Nonprofit, collaborative organization for scientists interested in probiotics and prebiotics
LPSN: List of Prokaryotic Names with Standing in Nomenclature
List maintained by J.P. Euzeby, Professor of Microbiology and Immunology, École Nationale Vétérinaire de Toulouse, France
Labeling & Nutrition: Food Labeling and Nutrition Overview
Resource for labeling requirements for foods under the Federal Food Drug and Cosmetic Act and its amendments
Max Rubner-Institut, Federal Institute of Nutrition and Food
Research institute comprising 135 researchers who focus on health and consumer protection in the nutrition sector
Minireview: A Special Fondness for Lactobacilli
Review article on lactobacilli published in Applied and Environmental Microbiology in 2004
Chen Y, Song KY, Brown EW, et al. 2010. Development of an improved protocol for the isolation and detection of Enterobacter sakazakii (Cronobacter) from powdered infant formula. J. Food Prot. 73: 1016-1022.
Cho GS, Huch M, Hanak A, et al. 2010. Genetic analysis of the plantaricin EFI locus of Lactobacillus plantarum PCS20 reveals an unusual plantaricin E gene sequence as a result of mutation. Int. J. Food Microbiol. 141 Suppl 1: S117-S124.
Gonzalez-Escalona N, Hammack TS, Russell M, et al. 2009. Detection of live Salmonella sp. cells in produce by a TaqMan-based quantitative reverse transcriptase real-time PCR targeting invA mRNA. Appl. Environ. Microbiol. 75: 3714-3720. Full Text
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Kostinek M, Ban-Koffi L, Ottah-Atikpo M, et al. 2008. Diversity of predominant lactic acid bacteria associated with cocoa fermentation in Nigeria. Curr. Microbiol. 56: 306-314.
Naum M, Brown EW, Mason-Gamer RJ. 2008. Is 16S rDNA a reliable phylogenetic marker to characterize relationships below the family level in the enterobacteriaceae? J. Mol. Evol. 66: 630-642.
Oguntoyinbo FA, Huch M, Cho GS, et al. 2010. Diversity of bacillus species isolated from okpehe, a traditional fermented soup condiment from Nigeria. J. Food Prot. 73: 870-878.
Ramsey KJ, Carter EC, McKee ML, et al. 2010. Reclassification of the Listeria-CAMP Test Strain ATCC 49444 Staphylococcus aureus as Staphylococcus pseudintermedius. J. Food Prot. 73: 1525-1528.
Ringel-Kulka T, Ringel Y. 2007. Probiotics in irritable bowel syndrome: has the time arrived? Gastroenterology 132: 813-816; discussion 816.
Ringel Y, Carroll IM. 2009. Alterations in the intestinal microbiota and functional bowel symptoms. Gastrointest. Endosc. Clin. N. Am. 19: 141-150, vii.
Sanders ME, Guarner F, Mills D, et al. 2005. Selected topics in probiotics and prebiotics: meeting report for the 2004 international scientific association for probiotics and prebiotics. Curr. Issues Intest. Microbiol. 6: 55-68.
Schillinger U, Boehringer B, Wallbaum S, et al. 2008. A genus-specific PCR method for differentiation between Leuconostoc and Weissella and its application in identification of heterofermentative lactic acid bacteria from coffee fermentation. FEMS Microbiol. Lett. 286: 222-226.
Whittaker P, Keys CE, Brown EW, et al. 2007. Differentiation of Enterobacter sakazakii from closely related Enterobacter and Citrobacter species using fatty acid profiles. J. Agric. Food Chem. 55: 4617-4623.
Whorwell PJ, Altringer L, Morel J, et al. 2006. Efficacy of an encapsulated probiotic Bifidobacterium infantis 35624 in women with irritable bowel syndrome. Am. J. Gastroenterol. 101: 1581-1590.
Xi M, Zheng J, Zhao S, et al. 2008. An enhanced discriminatory pulsed-field gel electrophoresis scheme for subtyping Salmonella serotypes Heidelberg, Kentucky, SaintPaul, and Hadar. J. Food Prot. 71: 2067-2072.
Yang B, Zheng J, Brown EW, et al. 2009. Characterisation of antimicrobial resistance-associated integrons and mismatch repair gene mutations in Salmonella serotypes. Int. J. Antimicrob. Agents 33: 120-124.
Yousif NM, Huch M, Schuster T, et al. 2010. Diversity of lactic acid bacteria from Hussuwa, a traditional African fermented sorghum food. Food Microbiol. 27: 757-768.
Zheng J, Keys CE, Zhao S, et al. 2007. Enhanced subtyping scheme for Salmonella enteritidis. Emerg Infect. Dis. 13: 1932-1935. Full Text
Linda Duffy, PhD
Linda Duffy, previously a professor of pediatrics and preventive medicine for 15 years, trained in preventive medicine and infectious disease epidemiology and has research interest in translational models and validation standards. She participated in the review of NIH Roadmap initiatives, including microbiome projects and other trans-agency initiatives, and currently serves as a program officer in the NCCAM Natural Products Branch. She oversees the clinical translational probiotics portfolio and is a member of the NIH Trans-agency Probiotics and Prebiotics Group.
Tri Duong, PhD
Tri Duong's research interests focus on the use functional genomic techniques to understand the probiotic functionality of lactic acid bacteria and their application in health and food safety. He received a PhD in Functional Genomics from North Carolina State University under the direction of National Academy of Science member, Todd R. Klaenhammer, and underwent postdoctoral training at Washington State University. Duong is an assistant professor at Texas A&M University in the Department of Poultry Science.
Marguerite Klein, MS
Marguerite Klein, whose academic training is in nutrition, health education, and clinical trials methodology, has had a 20-year career at NIH. In 2008, she joined the NIH Office of Dietary Supplements where she serves as the director of the Botanical Research Centers Program. She is also expanding the ODS Analytical Methods and Reference Materials Program and is working to address challenging issues (e.g., soy clinical studies; probiotic safety) in order to improve the integrity of dietary supplement research.
Dan D. Levy, PhD
Dan Levy supervises pre-market safety review of new dietary (supplement) ingredients for the FDA and chairs the FDA Ad hoc Inter-Center Workgroup on Live Microbial Ingredients. His research interests in the molecular genetics of FDA-regulated products are rooted in his background in DNA mutagenesis and repair starting from doctoral work at the NYU Sackler Institute, postdoctoral research at the National Cancer Institute in Bethesda MD and the Center for Nuclear Studies in Grenoble, France, and 15 years of research and regulatory experience at FDA.
Mary Ellen Sanders, PhD
Mary Ellen Sanders, through her business Dairy & Food Culture Technologies, consults on all aspects of probiotic applications in the food and supplement industries. She believes probiotics will flourish only if available products are scientifically validated, responsibly produced and accurately labeled. She strives to balance the potential consumer benefits of probiotics with an understanding of the emerging science. Based on her extensive work with manufacturers, academicians, and regulators, Sanders offers a comprehensive perspective to those interested in the continued emergence of the probiotic industry.
Howard Young, PhD
Howard Young, a principal investigator in the Cancer and Inflammation Program, Center for Cancer Research, National Cancer Institute-Frederick, studies the control of gene expression during the development and maturation of the cellular immune system with a special emphasis on Interferon-gamma expression by NK cells. Author/co-author of over 270 papers, Young was president, International Society for Interferon and Cytokine Research (2004–2005) and served as chair of the Immunology Division of the American Society for Microbiology. He has served as chair of the NIH Cytokine Interest Group and co-chair of the NIH Immunology Interest Group.
Neville Bamji, MD
Neville Bamji is a clinical instructor of medicine at the Mount Sinai Hospital, New York. He received his undergraduate degree in 1998 from Johns Hopkins University. He received his MD in 2002 from Cornell University Medical College. He subsequently completed internship and residency training in Internal Medicine in 2005 at the New York Presbyterian Hospital–Weill Cornell Campus. He then went on to complete his fellowship in gastroenterology in 2008 at New York Presbyterian Hospital–Weill Cornell Campus. His research interests include colorectal cancer screening and wireless capsule endoscopy. Bamji has presented his research at various national and international meetings.
Brian J. Beck, PhD
Brian Beck currently manages the acquisition, characterization and maintenance of more than 19,000 items in the Bacteriology collection at ATCC. He earned his PhD in microbial physiology at the University of Wisconsin–Madison and held applied research appointments at the University of Minnesota and University of Michigan. His interests range from the isolation and description of new isolates that produce natural products with therapeutic potential to targeting the biosynthesis of secondary metabolites such as siderophores in pathogenic bacteria for the development of new antimicrobials.
Eric W. Brown, PhD
Eric W. Brown is a research microbiologist with the Food and Drug Administration's Center for Food Safety and Applied Nutrition (CFSAN). Brown currently serves as the chief of the Molecular Methods and Subtyping Branch within the Division of Microbiology–Office of Regulatory Science and is actively engaged in a multi-parameter research program to develop and apply molecular genetic strategies for identifying and differentiating dangerous bacterial foodborne pathogens. Brown's expertise lies in the science of evolution and genetics where he has made important contributions toward understanding the evolutionary dynamics of several groups of bacterial pathogens that are significant in the fields of food, biomedical, environmental, and agricultural microbiology.
Brown received his PhD in Microbial genetics from The George Washington University. He then accepted a tenure-track faculty position in the Department of Biological Sciences at Loyola University of Chicago. In 2000, Brown moved to the Food and Drug Administration and has since carried out numerous experiments relating to the molecular detection and identification of foodborne pathogens. Brown has published findings in numerous peer-reviewed research journals and has presented data at many national and international meetings. He has been a member of the American Society for Microbiology since 1994 as well as the Willi Hennig Society of Systematics and Evolution since 1996. Recently, Brown authored a chapter on the molecular differentiation of bacterial strains presented in a book on Molecular Epidemiology published by Oxford University Press.
Duane L. Charbonneau, PhD
Procter & Gamble
Duane L. Charbonneau is a PhD microbiologist and a research fellow for Procter & Gamble's global personal health research and development team. With over twenty years of healthcare industry experience, he is an expert infectious agents and antimicrobial technologies for the consumer healthcare industry. In his role as research fellow, Charbonneau manages various components of the research and development programs, including in vitro methodology and testing as well as clinical trial design, execution and interpretation, literature review and product research. Charbonneau has authored over 25 published articles and holds several patents. Charbonneau received his PhD from Cornell University.
Richard L. Cleland, JD
Richard Cleland joined the Federal Trade Commission's Division of Advertising Practices in 1991. In 1996, Cleland was appointed assistant to the director of the Bureau of Consumer Protection and, in 1998, he was appointed assistant director of the Division of Service Industry Practices. He currently serves as assistant director of the Division of Advertising Practices. His primary area of expertise is the advertising and marketing of health-related products and services. He also supervises many of the Commission's health fraud and weight-loss product and service law enforcement initiatives. Current areas of interest include immunity claims for dietary supplements and foods. Cleland recently supervised the Commission's review of the Endorsement and Testimonial Guides. Prior to joining the Federal Trade Commission, Cleland served as special assistant attorney general and director of the Division of Consumer Protection in the Iowa Attorney Generals Office.
Charles Franz, PhD
Charles Franz is a microbiologist at the Max Rubner Institute (MRI), Federal Research Institute for Nutrition and Food, in Karlsruhe Germany. Franz earned his PhD at the University of Alberta, Canada, before moving to Germany to take up his position at the MRI, where he has been active in research and heads a laboratory for the last 12 years. Franz is a specialist on lactic acid bacteria, their physiology, genetics, taxonomy as well as probiotic aspects. He is currently a member of the International Committee on Systematics of Prokaryotes, Subcommittee on the Taxonomy of Bifidobacterium, Lactobaciollus and Related Organisms.
Geraldine A. June, MS
Geraldine June is the supervisor of the Product Evaluation and Labeling Team, Food Standards and Labeling Staff, Office of Nutrition, Labeling and Dietary Supplements (ONLDS), FDA. She began her career at FDA in 1987 as a research microbiologist developing methods for detecting enteric pathogens in foods. In 1996, June joined the Office of Food Labeling (reorganized into what is now ONLDS) where she worked on issues such as common or usual names, ingredient labeling, warning and safe handling statements, and use of non-nutritional claims such as "fresh" on foods. Currently, she supervises a team that develops policies and regulations on issues such as allergen labeling, irradiation labeling, warning and safe handling statements, labeling of bioengineered foods, and food standards of identity. June received her BS degree in microbiology from Howard University in Washington, DC and her MS degree in microbiology from George Washington University in Washington, DC.
Elizabeth B. Rahavi, RD
Elizabeth Rahavi specializes in providing science-based communications about nutrition, health and wellness. She has extensive knowledge in consumer understanding of nutrition and food safety and serves as the associate director, wellness, at the International Food Information Council (IFIC). Rahavi is responsible for monitoring and tracking media trends on nutrition issues, developing communication materials and promotion plans, and facilitating IFIC's outreach to opinion leaders. Rahavi is an active member of the American Dietetic Association, Food and Culinary Professionals practice group and is currently the Regional Networking Coordinator Liaison for the Dietitians in Business Communications practice group. She is also a member of the Institute of Food Technologists. She received her bachelors degree in Dietetics & Institutional Administration from Texas Woman's University, and completed her internship with Sodexho. She is also a registered dietitian and certified personal trainer. Rahavi is an avid yogi and runner, recently completed her second full marathon. Prior to joining IFIC Rahavi worked as a clinical dietitian in the Washington, DC metro area and as an assistant at Understanding Nutrition in Dallas, Texas.
Yehuda Ringel, MD
Yehuda Ringel has been involved in clinical and translational research related to functional gastrointestinal disorders for over 10 years. His research relates to the effect of clinical, physiological, and psychosocial factors on the intestinal function and functional GI symptoms. He has been involved in the design, evaluation, and conduct of clinical trials evaluating new drugs, food supplements, and other approaches for treatments of these symptoms.
Kenneth M. Taylor, PhD
U.S. Food and Drug Administration
Kenneth Taylor helps with developing regulatory policy for dietary supplements and related drug products to reconcile complex scientific matters with statutory requirements. This includes evaluating novel substances for use as potential dietary ingredients and the claims that are made about them for conformity with the Dietary Supplement Health and Education Act of 1994. He has been recognized by the Commissioner of Food and Drugs for his efforts to enhance enforcement activities against dietary supplement products that make misleading and fraudulent claims on the Internet. He received his doctoral degree in bochemistry from the Uniformed Services University of the Health Sciences, Bethesda MD.
Megan Stephan studied transporters and ion channels at Yale University for nearly two decades before giving up the pipettor for the pen. She specializes in covering research at the interface between biology, chemistry and physics. Her work has appeared in The Scientist and Yale Medicine. Stephan holds a PhD in biology from Boston University.
Probiotics have been available since ancient times in fermented foods such as cheese, yogurt, sauerkraut, and pickles. Today, the health properties of foods containing probiotics are receiving increased attention from consumers who are interested in improving their health by improving their diets. The identities of the microorganisms in these foods have been known in many cases since the 19th and 20th centuries, but with the advent of molecular biological techniques our capacity to characterize them has increased greatly. These techniques make it possible for probiotics makers to ensure the quality and safety of their products more rigorously than ever before. At the same time, the industry is receiving increased scrutiny from regulatory officials, who are charged with ensuring that these products contain what they say they do, and provide the benefits that are described on labels and in advertisements.
In June 2010, manufacturers of probiotics products, regulatory officials, microbiologists, and others with an interest in probiotics labeling met to discuss this aspect of the industry. Representatives of regulatory agencies, including the U.S. Food and Drug Administration (FDA) and the Federal Trade Commission, laid out current agency guidance and discussed the precedents set by similar products in developing standards for probiotics labeling and advertising. In later sessions, microbiologists described how best to use recent scientific advances to identify and characterize the microorganisms present in probiotic foods and supplements. Such measures will provide assurance to consumers and regulatory officials alike that probiotic products contain the organisms that are described on their labels.
In the first session of the conference, experts discussed evolving standards for claims made about probiotics, consumer awareness and acceptance of probiotics, and considerations for labeling and advertising. Yehuda Ringel of the University of North Carolina at Chapel Hill discussed approaches to substantiating claims that probiotics improve digestive health, a challenging topic since there is currently no consensus on what constitutes good digestive health. Elizabeth Rahavi of the International Food Information Council described the results of consumer surveys conducted by her organization that document the growing awareness of probiotics among consumers. Kenneth Taylor of the Center for Food Safety and Applied Nutrition at the FDA explained FDA guidance on what constitutes acceptable substantiation of structure-function claims for probiotics produced as supplements. Richard Cleland of the Federal Trade Commission described regulatory standards for advertising and how they apply to probiotic products.
The second session focused on standards for labeling and identifying the bacterial strains present in probiotics. Geraldine June of the FDA Center for Food Safety and Applied Nutrition described FDA standards for food package labeling and how these standards should be applied to probiotics. Charles Franz of the Max Rubner-Institut, Federal Institute of Nutrition and Food in Germany, described recent developments in bacterial taxonomy that affect how probiotics species are named and how they should be identified on product labels. Brian Beck of the American Type Culture Collection discussed his organization's role in archiving, identifying, and maintaining culture stocks of commercially important bacterial strains, including probiotics. Eric Brown of the FDA described the difficulties inherent in identifying, defining, and naming bacterial strains and their implications for the probiotics industry; and Duane Charbonneau of Procter & Gamble provided an industry perspective on these difficulties. These speakers also provided an overview of the molecular biological tools that could be brought to bear to resolve these issues.
Mary Ellen Sanders, Dairy and Food Culture Technologies
Yehuda Ringel, University of North Carolina at Chapel Hill
Elizabeth B. Rahavi, International Food Information Council
- Substantiation of claims that probiotics improve digestive health will require careful attention to the definition of digestive health as well as carefully designed human trials using appropriate endpoints and trial populations.
- Surveys show that most American consumers are aware of the health benefits of specific foods, including probiotics, but fewer have adopted dietary changes based on this knowledge.
Approach for substantiating a claim of digestive health for probiotics
One of the primary health benefits attributed to probiotics is the ability to relieve or prevent common digestive problems, such as constipation, diarrhea, and bloating. While there is significant anecdotal evidence for such benefits, to date very few human studies have examined in a controlled fashion whether probiotics improve the digestive health of healthy individuals who consume them. The results of such studies play an important role in allowing probiotics makers to disseminate information about the benefits of their products, while still complying with government regulations. Gastroenterologist Yehuda Ringel of the University of North Carolina at Chapel Hill provided a specialist's perspective on what is needed to substantiate claims of digestive health benefits for these products.
Many consumers are interested in improving their health through diet, which includes using probiotics as foods that are intended to improve the normal function of the body. Probiotics are also marketed as over-the-counter dietary supplements, with the implication that consumption will promote digestive health and reduce or prevent problems such as constipation and diarrhea. Ringel noted that consumers using the internet can find considerable advice on maintaining digestive health and dealing with digestive symptoms by using supplements or ingesting foods containing probiotics. However, the advice presented varies from site to site and is not always supported by clinical evidence. Surveys have also found that, despite manufacturers' recommendations, very few consumers consult a health care professional before making use of probiotics.
At the same time, health care professionals are very limited in the advice that they can dispense about these products, since the lack of clinical evidence translates directly to a dearth of professional guidance in this area. Neither professional societies, such as the American Gastroenterological Society, nor government agencies, such as the USDA, have provided specific, detailed recommendations for the uses of probiotics. The recent Rome III handbook on functional bowel disorders, considered the most comprehensive reference in this area, is over 1000 pages long but includes only two paragraphs on probiotics.
Clinical researchers who are working to fill this evidence gap for probiotics face a number of challenges, including how best to define the condition that they are studying, and how to choose an appropriate population in which to study probiotics' effects. Many common ailments of the bowel are not really diseases but instead are ongoing conditions that are defined primarily by groups of symptoms, such as constipation together with bloating, or diarrhea and pain. Patients with these conditions are primarily seeking relief from their experience of these symptoms.
Researchers designing clinical studies can choose to use these symptoms as endpoints, or they may elect to use more readily quantifiable measures, such as physiological parameters of gut function or biomarkers. Unfortunately, however, very little is known about clinical relevance of such measures. For example, colonic transit time is thought to be related to constipation, but up to 59% of constipated patients have normal transit times. In addition, while promotion of "digestive health" is often mentioned as a reason for taking probiotics, this concept is not a defined or measurable endpoint that can be used in studies intended to produce clinical evidence.
Researchers must also choose the population in which to test probiotics. They may choose to do their studies in healthy individuals, in otherwise healthy individuals who have a high rate of digestive symptoms or abnormal bowel function, or in individuals with disease states such as irritable bowel syndrome. Patients with gastrointestinal symptoms can vary considerably in the severity of their conditions, so it is important that the study population be chosen so that results can be generalized to the intended target population for a specific probiotics product.
Ringel said that preclinical studies, as well as the few human studies that have been done, strongly suggest that there is a scientifically based rationale for targeting the intestinal microbiota with probiotics in order to relieve the functional symptoms of digestive disorders. It is now the task of researchers in this area to carefully design the studies that will provide firm evidence, with the support of public and private funders to provide the necessary resources, and with the assistance of government regulatory bodies, who must agree amongst themselves and provide clear regulatory expectations for the industry.
Communicating the benefits of foods that can promote health
The International Food Information Council (IFIC) is an industry organization that provides science-based communications about food safety and nutrition issues to health professionals, journalists, and others with an interest in this area. Recent years have seen a rapid rise in media coverage of functional foods, including probiotics, and their relationship to health. The IFIC has conducted surveys investigating American consumers' opinions on the relationships between diet and health, their knowledge of functional foods, and their primary sources of information about food and nutrition. Elizabeth Rahavi of the IFIC reported on the results of two such surveys, conducted in 2009 and including over 1000 U.S. adults, and the implications of these results for manufacturers of probiotic products.
The surveys explored consumer attitudes about health issues in general, and as they relate to functional foods. The results show that 91% of Americans feel they have some control over their health, with the majority agreeing that food and nutrition can play a large role in improving overall health. About two-thirds reported making changes to improve the healthfulness of their diet, in line with the top health concerns, which were heart disease, cancer, and weight management.
Most Americans agreed that certain foods have health benefits that go beyond basic nutrition. Compared to a previous survey in 1998, the number of Americans who could name a functional food and its associated health benefit rose from 77% to 92% in 2009, demonstrating markedly increased awareness. Of interest to probiotics makers, many mentioned dairy, including milk and yogurt, when asked to name a functional food. Fiber was also one of the most frequently recognized functional food components with digestive health benefits.
The survey asked people about their awareness of certain food-health benefit pairings, including probiotics for maintaining a healthy immune system, and probiotics for digestive health. Awareness of these health benefit pairings rose substantially from around 56% in 2007 to 72% in 2009, in keeping with the recent high profile of probiotics in the media. However, only 25%–60% of American consumers in the more recent surveys said that they were consuming any particular food for a specific health benefit.
Most respondents (85%) expressed an interest in learning more about foods with additional health benefits, suggesting that interest levels remain quite high. The top sources that individuals used to get information on functional foods included the media, food labels, and family and friends. Only about one-third used health professionals as a major source of information. Previous research had shown that many consumers don't understand the regulatory framework involved in making health claims, and most favor structure-function claims because they are positive and easy to understand.
In addition to the surveys, the IFIC has published peer-reviewed journal articles that provide guidance to industry on how to translate these findings into messages that will most effectively assist consumers with their decisions on food and nutrition. Their advice emphasizes that building a sense of empowerment and competence among consumers with regard to their food choices, while providing information that is clear and actionable, will be the key to promoting more healthful diet practices among Americans.
Mary Ellen Sanders, Dairy and Food Culture Technologies
Kenneth M. Taylor, Center for Food Safety and Applied Nutrition, U.S. FDA
Richard L. Cleland, Federal Trade Commission
- Current FDA guidance describes the quality of scientific evidence that is necessary to make structure-function claims, including research in humans that is consistent, scientifically sound, and directly related to the desired claim and the product formulation.
- Standards for substantiating advertising claims for probiotics are similar to those for substantiating label claims, requiring truthful information that is not misleading.
Substantiating structure/function claims made for dietary supplements
Kenneth Taylor of the U.S. FDA provided a regulatory perspective on substantiating the structure-function claims that the IFIC surveys suggest are favored by consumers. Taylor noted that the number of new food ingredient notifications that include probiotics has risen sharply in recent years, providing a regulatory challenge for the FDA, which must act in the absence of substantial clinical evidence. In most cases there is not enough evidence to make health or drug claims for these new ingredients. When used as dietary supplements, probiotics are limited to claims that they either assist with classical nutrient deficiency diseases, have effects on the structure or function of the body, or support general well-being. While such claims do not require prior FDA review or approval, they must still be carefully substantiated to ensure that they are truthful and not misleading.
In December 2008, the FDA published guidance that describes the amount, type, and quality of evidence that the agency is looking for when substantiating claims for dietary supplements. Taylor emphasized that there is no pre-established formula for substantiating a claim. The agency will accept a variety of types of evidence but is primarily looking at whether the evidence comes from competent and reliable studies that have been conducted and evaluated objectively by professionals in the relevant area. Probiotics makers should consider four areas when putting together evidence for substantiation: the meaning of the claim being made, the relationship between the claim and the available evidence, the quality of the evidence, and whether the totality of the evidence supports the claim. If a particular claim has more than one possible interpretation then each possible interpretation must also be substantiated.
Evidence must be directly related to the claim. Taylor provided an example of a claim that would not be considered substantiated. A substance that produces an increase in metabolism in study subjects in a randomized controlled double-blind study cannot claim that it "promotes weight loss" unless there is additional research directly correlating the increase in metabolism with weight loss.
Evidence must also be obtained with substances that are similar in formulation, route of administration, and other physical characteristics in order to be used to substantiate a claim for a particular product. Thus studies done with conventional foods are not applicable to individual dietary supplements, and studies of substances applied topically are not applicable to supplements taken by mouth. Manufacturers must account for the roles of other substances present in the product that could potentially be responsible for the effect claimed for the probiotic ingredient.
When gathering evidence, it is also important for probiotics makers to consider whether each study was well designed, carried out effectively, and analyzed carefully, as well as whether it used an appropriate test population. Studies should be performed in humans rather than test animals. Interventional studies, where the researcher controls subject exposure to the product, are considered to provide better evidence than observational studies. Background information, including animal studies, anecdotal evidence, and meta-analyses of clinical research, can be used to help support the claim but these types of data are not enough to be considered adequate substantiation by themselves.
Taylor said that manufacturers must perform a critical evaluation of all available evidence, including evidence that is unfavorable, to determine what the totality of the evidence shows regarding a particular claim. Overall, the data should be mostly consistent with the claim, and manufacturers should provide explanations for any inconsistencies or conflicting results. In providing this guidance, the FDA has tried to set expectations and standards that are uniform but still flexible enough to consider a variety of types of evidence. Probiotics manufacturers who adhere to this guidance and provide high quality evidence will avoid regulatory difficulties and contribute to increased consumer confidence in the labeling claims made for their products.
Substantiation of health claims in advertising
While the FDA has jurisdiction over the labeling of foods and dietary supplements, the Federal Trade Commission, or FTC, has jurisdiction over how these products are advertised. The FTC does not necessarily use the same rules, and may not take the same position on the science behind product claims, but they do try to be consistent with the FDA whenever possible. The FTC acts under legislation that prohibits unfair or deceptive practices affecting commerce, including the dissemination of false advertising, ads that make false or unsubstantiated claims, and ads that fail to disclose material facts that would influence the consumer's decision whether or not to buy a particular product.
Similar to the FDA, the FTC requires substantiation for objective product claims in advertising, including those made about foods and dietary supplements. The advertiser of a product is required to have the information needed to substantiate the claim prior to dissemination of the advertisement. Advertisers must provide facts that support their contention that a claim is true or it will be considered false. Relevant factors include the level of evidence claimed in the ad (for example if the ad claims that clinical studies showed a certain benefit then this must be true), the type of claim, the consequences of a false claim for the consumer, and the benefits of a truthful claim.
The FTC also takes into account the amount of substantiation that experts in the field believe is reasonable for a given product. Health claims in advertising require competent and reliable scientific evidence from studies conducted by experts, and the totality of the evidence must support the claim. Therapeutic claims must be supported by one or more human clinical trials of appropriate design. Products that only work in a subset of the population must be clearly identified as such in advertisements.
Cleland noted that because probiotics are becoming increasingly well known and popular, there is likely to be increased scrutiny of products and the claims made about them. "Regulatory standards will be high and require science that is good," he said.
Dan D. Levy, U.S. Food and Drug Administration
Geraldine A. June, Food Labeling and Standards Staff, FDA Center for Food Safety and Applied Nutrition
Charles Franz, Max Rubner-Institut, Federal Institute of Nutrition and Food
- The FDA has set specific rules for food product and dietary supplement labeling that should be applied to probiotics, including required information such as ingredients, nutrition facts, and allergens present.
- Probiotic product labels should include the genus and species of the microorganisms present, a task that is complicated by frequent reassignment of species within the bacterial nomenclature.
- Careful attention to the identities of probiotics strains will ensure their safety and efficacy and facilitate makers' interactions with regulatory agencies like the FDA.
FDA ingredient labeling regulations
In addition to regulating structure-function and other claims about foods and dietary supplements, the FDA is responsible for providing rules about how these products are labeled, including mandatory elements, such a statement of identity (the name of the food) and the naming and listing of ingredients. Labels are also required to include information about the amount of food in the package, the name and address of the business producing the food, nutritional content, allergens, and other information important to consumers.
FDA regulations require that foods be named with common or usual names that are uniform among similar products and that accurately identify the type of food. These names are established by regulation, by guidance or letter after consultation with the FDA, or by common usage. Ingredient labeling also uses common or usual names, which must be listed in descending order of predominance by weight. Flavors, spices and incidental additives that do not contain major food allergens are exempt from specific mention in the ingredients list.
Several of these rules for labeling are likely to be particularly important in their application to probiotics, including specific rules for the labeling of microorganisms and products derived from microorganisms. Bacterial cultures found in foods are named in relation to the culture substrate, for example, cultured skim milk. If a specific species is mentioned, Latin binomial names should be used according to internationally accepted nomenclature, following the standards set by the naming of botanicals, generally found in dietary supplements. As for other ingredients, the naming of probiotics should be consistent with general rules for common or usual names and should be uniform throughout the industry for similar ingredients. The name of a bacterium sold as such should be the same name as is found in the list of ingredients. Labels that follow these rules will provide consumers and health professionals with accurate information that assist them with their purchasing decisions and recommendations to patients.
Recommendations from Lactobacillus and Bifidobacterium nomenclature committees
As probiotics are distributed and used more widely, it is important that there be consistency in how the microorganisms in these products are named, not just from a regulatory standpoint but from clinical and consumer perspectives as well. Charles Franz, of the Max Rubner-Institut Federal Institute of Nutrition and Food in Germany, provided recommendations for the nomenclature of probiotic strains based on current taxonomic standards.
Bacteria are remarkably diverse, falling into more than 70 phyla. In addition to this diversity, bacterial taxonomy is somewhat fluid, changing frequently as more species are characterized and more genomes are sequenced. Fortunately most probiotics are members of just two phyla, the Firmicutes, which include the Lactobacillaceae, the Enterococcaceae, and the Bacillaceae, and the Actinobacteria, which includes the Bifidobacteriaceae.
Some areas of bacterial taxonomy are currently considered unsatisfactory and are particularly subject to change as researchers gather more information. The lactobacilli form a highly complex and varied group of microorganisms, including over 130 species whose molecular characteristics are much more diverse than is generally accepted for a taxonomic grouping. This diversity probably reflects the diverse origins of the lactobacilli, with some groups derived from the gut, while others were isolated from food or the environment. The genus Bifidobacterium is a similarly large and confusing family that has undergone recent taxonomic updates.
Because bacterial species names often change, particularly in very large families, it is important that probiotics makers keep current with the field. They should use taxonomically correct names that include up-to-date genus and species designations whenever possible. Several studies have found that many of the species found in probiotics are misidentified, or their names have not been updated to new taxonomic specifications, including many Lactobacillus and Bacillus species. Franz provided information on a number of websites and other sources of information that manufacturers can use to keep up to date on bacterial nomenclature.
Beyond the genus and species level, many bacterial isolates are given a strain name that can be based on any of a number of specific characteristics. The strain name is not subject to taxonomic rules and can be made up by the producer or discoverer of the strain. Franz said that it is important that the strain name not mislead consumers as to the functional properties of the bacterium. Some probiotics are also given trade names, which is considered acceptable if the product description also includes the proper taxonomic names of the microorganisms included. In addition to appropriate naming, new strains should be stored properly to protect their integrity, including the use of master cultures that are kept at −80° C and deposit of the strain in an independent culture collection such as the American Type Culture Collection.
Dan D. Levy, U.S. Food and Drug Administration
Brian J. Beck, American Type Culture Collection
Eric W. Brown, U.S. Food and Drug Administration
Duane Charbonneau, Procter & Gamble
- Biological resource centers like the American Type Culture Collection can assist probiotics makers in preserving and maintaining the integrity of probiotic bacterial strains.
- These bacterial strains should be carefully characterized by biochemical, microbiological and molecular biological methods to ensure that they retain their identity over time.
International biological resource centers
The subject of strain storage and preservation was expanded upon by Brian Beck of the American Type Culture Collection, or ATCC. Often it is difficult to maintain the purity of biological materials, especially living organisms like bacteria, in a busy laboratory or manufacturing facility where many liters of culture are grown and harvested on a daily or weekly basis. Bacterial strains change, accumulating mutations as they go through repeated cycles of culture inoculation and growth. They may also become contaminated with or taken over by unwanted interlopers. Thus there is a continual need for bacterial strains to be archived and their identities carefully verified over the passage of time. This process is especially important for strains that are intended to be used for human consumption and/or for clinical purposes, as are probiotics.
Biological resource centers such as the ATCC facilitate the archiving and curation of bacterial strains and other biological resources for scientific and commercial organizations. The ATCC is a private independent nonprofit organization that acquires, archives, and develops biomaterials to support applied and basic research by worldwide distribution. They authenticate the material in their collection and produce stock cultures that preserve bacterial strain for future use. In addition to bacteria, the ATCC stores such materials as cultured eukaryotic cells, viral and fungal strains, and nucleic acids. The ATCC also produces reference standards for many types of laboratory tests.
Researchers and other users of bacterial strains can deposit their biological materials for safekeeping with the ATCC according to four different types of options. They can deposit strains into the general collection at no cost, although there is a fee when cultures are distributed. The ATCC holds contract collections for a number of research organizations, including the Human Microbiome Project and the Centers for Disease Control. The ATCC also serves as an International Depository Authority for the deposit of biological material for use in patenting. These materials are released for public distribution only after the patent is issued, and the patent holder/depositer is notified when they are requested. Finally, the ATCC can hold strains in a Safe Deposit collection for release only to the organization or individual that deposited them, which may include, for example, companies that are developing specific bacterial strains for commercial purposes.
Because it is charged with safekeeping these strains, the ATCC maintains very high quality standards for culture production and identification, including polyphasic testing and the use of public databases to ensure the identity of organisms in the collections. Cultures are preserved to be as close as possible to the original culture and carefully authenticated before distribution. Tests such as morphologic screening, biochemical testing, and physiological analyses, are combined with molecular typing methods, such as sequencing of target genes, to verify the identity of the culture as precisely as possible. Each strain is identified by multiple methods and the results of such testing are compared with known information supplied by the depositor, taken from public and private databases, or gleaned from the scientific literature. These activities play a critical role in ensuring the purity and safety of the bacterial strains that are used in research and industry, including those used in probiotics.
Delimiting the boundaries of the "strain" in an ever-evolving bacterial world
As living organisms, bacteria are constantly changing and adapting to their environment, leading to changes in their phenotypic expression patterns. Such changes can make it difficult to pin down a bacterial strain as having a hard and fast identity and a fixed set of characteristics. However, the growing use of live bacterial strains in foods and supplements has made it increasingly important to identify and name strains of bacteria accurately.
There are multiple definitions as to what constitutes a bacterial strain. A strain is usually considered to be a subset of a bacterial species that differs by some minor but readily identifiable characteristic. Strains may also be considered bacterial cultures that have arisen from a single organism or from a pure culture isolate. Strains can vary from one another in many ways, including clinically or industrially important characteristics such as differences in antibiotic resistance, virulence, and/or responses to culture conditions such as temperature or pH.
Many different types of attributes are used to distinguish among bacterial strains, including genotypic, phenotypic, morphotypic, and other differences. The type of difference that identifies the strain often dictates the strain name, for example a strain that is a serovar is differentiated by serological methods, and a pathovar is differentiated by pathogenic characteristics. The first or most well-studied strain of a species is generally considered the "type" strain to which others are compared, although this is not always the most representative strain of the species.
Brown described a number of molecular biological methods that can be used to identify bacterial strains, including pulsed field gel electrophoresis of restriction digests, optical mapping of DNA markers, DNA fingerprinting, and whole genome sequencing with SNP analysis. Strain differentiation is particularly important in food safety, where strains that are responsible for food poisoning outbreaks can be very similar to non-outbreak strains. The use of methods that detect very small differences among bacteria, whether beneficial or harmful, is the key to identifying strains effectively. Probiotics makers should first characterize their strains very carefully, and then follow their characteristics with time to ensure that they have not lost their beneficial properties or gained harmful ones.
Naming and marketing of strains—an industry perspective
Duane Charbonneau of Proctor and Gamble further elaborated on the reasons why it is important to properly identify the species and strains of the microorganisms included in probiotics. Like Brown, he recommended that the principles and practices used to identify and characterize foodborne pathogens be applied to probiotics to ensure careful designation and documentation of novel strains. He noted that regulatory compliance can be affected by taxonomic changes, because such changes could potentially change whether a dietary ingredient is considered new or whether it has already been accepted by the FDA. Probiotics makers can use these careful practices to establish that their strain is novel, while at the same time showing how it is related to strains that have previously been determined to be safe. Such practices are also needed to ensure the continued purity and safety of established probiotic products as they are marketed, and to ensure that the strain in the product is the same strain that was clinically tested.
Charbonneau expanded the list of molecular biological and biochemical tools that can be used to make these analyses. Traditional microbiological and biochemical techniques, such as substrate utilization, enzyme profiles, and protein analysis, still have a place in species and strain characterization. Nucleic acid based techniques that can be used include DNA/DNA hybridization, restriction digest based analyses, and sequencing of target genes or whole genomes. In the future, advanced methods such as systems microbiology, proteomics, glycomics, and metabolomics are also likely to play an important role in species and strain characterization.
While there are guidelines and rules for naming bacterial species, there are no such rules for naming strains. Often these names fail to provide important additional information about a particular bacterial isolate. Genus and species names often change as well as research continues. Charbonneau suggested that the use of trade names might alleviate some of these issues by staying constant even when the underlying species and strain was renamed. He emphasized that trade names would need to be carefully chosen to be reflective of the organism or its proven benefits and not misleading, based on the regulatory class of the claims made for a particular product. Such names can provide needed continuity for the consumers purchasing these products.
At the same time, scientific names, including strain designations, should also be kept on labels, he said. A process is needed for making name changes and for connecting the new names with existing and historical literature that uses the old names. Regulatory guidance will be needed to define the proper actions that should be taken when a bacterial name is changed or further refined, to ensure that consumers, health professionals and others are provided with consistent information about probiotics products.